As part of our Laboratory's (LMC) work on the elucidation of the structure and function of neurotransmitter systems in the mammalian central nervous system (CNS) and the molecular mechanism of action of CNS active drugs, a multidisciplinary approach is utilized in our studies which require synthesis of novel agonists, antagonists, imaging agents, affinity ligands and other drugs for particular applications. In one aspect of this work, approaches to opioid receptor selectivity based on unusual modifications of various opioid ligands were studied. We have learned that the delta and mu opioid receptors have similar requirements for ligand interaction; most ligands which effect one also act on the other. We have found that modification of the A-ring of 4,5-epoxymorphinans, known to have good affinity for mu opioid receptors, can lead to ligands with altered specificity. We have also found that modification of the substituent on the nitrogen atom of opioid ligands, some of which are well-known to change opioid agonists to opioid antagonists, may also modify the selectivity of the ligand to an opioid receptor subtype. Opioid binding assays for this study are ongoing, in collaboration with units of the Drug Evaluation Committee, a public service consortium affiliated with the College on Problems of Drug Dependence.